Altered signaling by neuromodulators, such as neuropeptides, are linked with debilitating human brain diseases including anxiety and panic disorders, schizophrenia, and epilepsy, yet we have a surprisingly limited understanding of how neuromodulators shape proper neural circuit function. How do neuromodulators produce specific patterns of neural circuit activity and how do changes in circuit activity produce specifi behavioral states? Our aim is to dissect molecular and neuronal mechanisms by which a conserved neuromodulatory system functions to shape neural circuit activity and behavior in response to changing sensory information (context). We have recently demonstrated that the neuropeptide NLP-12, a C. elegans ortholog of mammalian cholecystokinin (CCK), regulates context-dependent transitions between behavioral states, and we have begun to define the neural circuit basis for these effects. CCK is among the most abundant neuropeptides expressed in the mammalian brain, and CCK knockout mice display heightened anxiety, yet we do not have a clear understanding of how CCK functions in the context of the circuits that it modulates, or how CCK-mediated changes in activity alter anxiety levels. We are now well-positioned to gain a completely new level of understanding of how CCK shapes circuit activity and behavior, using the circuit we have defined in C. elegans as a model. We have developed tools for cell-specific manipulation of NLP-12/CCK levels, and for optogenetic stimulation and inhibition of NLP-12/CCK-expressing neurons. Further, we have defined 2 receptors, CKR-1 and CKR-2 that are required for NLP-12/CCK activity, and share significant homology with mammalian brain CCK1 and CCK2 receptors. In the first aim, we will determine how NLP-12 release from the interneuron DVA cooperates with descending sensory information (e.g., from olfactory neurons) to initiate context-dependent changes in behavioral output. In the second aim, we will define the circuitry involved and investigate how CKR- 1 and CKR-2 modulate the activity of the neurons in which they are expressed. By making a detailed functional investigation of a conserved neuromodulatory system in the context of this powerful model circuit, and linking functional changes to transitions between behavioral states, we expect to achieve a completely new level of understanding of how neuromodulators, in particular CCK, regulate neural circuit activity and modify behavior. We anticipate our findings will accelerate a path toward the development of effective therapeutic approaches for brain disorders associated with altered neuromodulatory signaling.